During sensitization (IgE), desensitization of IgE/MC reactivity
to the hapten-carrier complex develops
A cornerstone of the new interpretation of (drug) allergy is the
hypothesis that the sensitization of MC by a gradual increase of
specific IgE in the presence of antigen reduces MC reactivity to the
specific antigen (1) (table 2, figure 2). The underlying mechanism of
this antigen-specific unresponsiveness is not clear. It could be
similar or identical to the process of drug desensitization: Inin-vitro models it has been shown that this antigen-specific
process blocks calcium flux, impacts the antigen/IgE/FcεRI
complex-internalization and prevents the acute and the late-phase
reactions as well as mast cell mediator release (20). Importantly, this
unresponsiveness of MCs is specific for the antigen-IgE complex, while
MC-reactivity to other antigens by IgE cross-linking persists. The MC
unresponsiveness just covers the antigen concentration used for inducing
unresponsiveness, normally determined by the serum concentration of the
drug. When the MCs that carry specific IgEs are confronted with a
suddenly higher concentration of specific antigen than the tolerizing
dose, the unresponsiveness of MCs is broken and the MCs
react/degranulate. This phenomenon is known as “breakthrough reaction”
in drug desensitizations. It occurs, when the last increase of the drug
concentration was too large (21). When no antigen exposure occurs, this
MC-unresponsiveness is decreasing over time and an allergic reaction may
re-appear to previously tolerated antigen concentrations:
MC-unresponsiveness can be re-adjusted by a natural exposure: e.g. the
first bee stings in spring in already sensitized beekeepers may cause
urticaria, but these generalized reactions to stings disappear in the
following weeks (table 2) (22) and may also disappear by intended
antigen-exposure (“immunotherapy”) (22,23).
Importantly, this MC-unresponsiveness may represent the normalresponse when IgE is formed to protein antigens (allergens) and the
antigen is still present (table 2). It is different from the
long-lasting T cell-based tolerance mechanism (24), as it is based on
the unresponsiveness of MCs and probably also basophils, both carrying
IgE-FcεRI. The concept of MC-unresponsiveness also implies that at least
one scope of allergen-specific IgE is to react via MC to alocally relatively high allergen concentration, but not to
normal, systemically available levels of allergen.
MC-unresponsiveness could also explain the high number of sensitized but
not allergic individuals in various studies on the prevalence of
allergic diseases (25). Sensitization is often identified by positive
skin tests (prick, i.d.), where locally an excess amount of allergen is
applied (26). The concentrations used for skin tests break
MC-unresponsiveness and results in a local wheal and flare reaction.
Since epidemiological studies revealed that about half of the skin
test-positive individuals do not show symptoms to pollens (seasonal
rhino-conjunctivitis), they may be unresponsive to the usual
concentrations of pollen allergens reaching the tissue (26, 27).
However, they react to the high local allergen concentrations applied in
skin tests. This suggests that the difference between allergic
(sensitized and symptomatic) and sensitized (but asymptomatic)
individuals is that the amount of allergen reaching the tissue is higher
in allergic individuals. More likely seems that in allergic individuals
the IgE coated MC react to lower local concentrations of allergen; IgE
mediated allergy is thus a) defined by the formation of antigen-specific
IgE, and b) the MC-(un)responsiveness to the antigen/allergen
reaching the tissue is not well adjusted.